title: [Effect of a novel tyrosine kinase inhibitor HHGV678 on growth inhibition of Bcr-Abl wild type and IM-resistant cell lines in vitro].
abstract: This study was aimed to compare HHGV678 with imatinib (IM) in growth inhibition of Bcr-Abl wild type and IM-resistant cell lines, investigate the possibility of replacing IM with HHGV678 in treatment of chronic myeloid leukemia (CML) and IM-resistant CML patients. Viability of two Bcr-Abl wild type cell lines (K562 and 32Dp210) and 16 IM-resistant cell lines (K562R and 15 Bcr-Abl point mutant cell lines) treated with HHGV678 and IM was analyzed by MTT. The apoptosis of those cells was identified by flow cytometry with Annexin V staining and DNA ladder analysis. Western blot was applied for detecting the expression of Bcr-Abl and phosphotyrosine protein levels. The results indicated that HHGV678 significantly inhibited the growth of two Bcr-Abl wild types and IM-resistant cell lines in dose-dependent manner except cell line of T315I point mutant. IC(50) results showed that the growth inhibition of HHGV678 was 15.5 and 28-fold higher than that of IM in K562, 32Dp210 and 1.4 to 124.3-fold higher than that of IM in 15 IM-resistant cell lines respectively. Compared with IM, HHGV678 more significantly inhibited phosphotyrosine kinase protein of the cells mentioned above at different concentrations. With most importance, HHGV678 of 10.0 micromol/L induced cell apoptosis of 40.06% and 33.32% in K562R and 32Dp210(T315I) cell lines, which were much higher than that of IM (19.77% and 10.68%). It is concluded that HHGV678 is more effective than IM in the growth inhibition of Bcr-Abl wild type cell lines and IM-resistant cell lines, especially in strongest IM-resistant cell lines. Further studies are needed to show whether HHGV678 may be a novel targeting drug in treatment of CML and IM-resistant CML patients.
authors.affiliation: Harbin Institute of Hematolgy & Oncology, Harbin 150010, Heilongjiang Province, China. qiulin@csco.org.com
authors.forename: Lin
authors.initials: L
authors.lastname: Qiu
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Wang
authors.forename: Bo-Hai
authors.initials: BH
authors.lastname: Yu
authors.forename: Ren-Zhang
authors.initials: RZ
authors.lastname: Lu
authors.forename: Fang
authors.initials: F
authors.lastname: Ge
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Wang
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Chen
authors.forename: Bing-Hong
authors.initials: BH
authors.lastname: Han
authors.forename: Zhao-Ming
authors.initials: ZM
authors.lastname: Zhan
authors.forename: Bo-Long
authors.initials: BL
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
mesh_terms: D000631:Aminopyridines; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C553360:flumatinib